Airway mucus hypersecretion in asthma: an undervalued pathology?
Introduction
Airway mucus hypersecretion is an undervalued pathology. It has long languished as the ‘ugly sister’ to bronchoconstriction and eosinophilic inflammation in research into the pathophysiology of asthma. However, epidemiological studies demonstrate that mucus is a far from innocent disorder [1]. Indeed, current guidelines on asthma management highlight mucus plugging (Figure 1) alongside bronchoconstriction and inflammation as a cause of airway obstruction and airflow limitation [2]. Consequently, it is important to understand the pathophysiology of mucus hypersecretion in asthma. This should allow identification of therapeutic targets and subsequent rational development of pharmacotherapeutic drugs. This review focuses on the pathophysiology of mucus hypersecretion in asthma by, firstly, describing the mucus hypersecretory phenotype as it pertains to asthma; secondly, assessing the pathophysiological consequences and clinical impact of mucus hypersecretion in asthma; and thirdly, considering the epidemiology of mucus hypersecretion in asthma. The article finishes by outlining conventional and novel therapies for this condition.
Section snippets
Airway mucus
In healthy individuals, a film of slimy liquid protects the airway surface from inhaled ‘insult’ [3•]. The liquid is referred to as ‘mucus’ and is a complex non-homogeneous dilute (1–2%) aqueous solution of electrolytes, endogenous and exogenous proteins, lipids and carbohydrates. Mucus forms an upper gel layer and a lower sol layer. Inhaled particles are trapped in the gel and, by transportation on the tips of beating cilia, are removed from the airways: a process termed mucociliary clearance.
Mucus hypersecretory phenotype in asthma
Airway mucus hypersecretion in asthma has characteristic pathophysiological features. Many of these features, such as sputum production and goblet cell hyperplasia, are common to other hypersecretory respiratory diseases; for example, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Other features appear to be specifically associated with asthma (see below). Differences in mucus pathophysiology between asthma and COPD have been discussed previously [7], and are summarized in
Pathophysiological consequences of mucus hypersecretion and hyperviscosity
The previous section established that there is overproduction of hyperviscous mucus in asthmatic airways. Depending upon how much is present, increased mucus in the airway lumen might not noticeably affect airflow (Figure 6). Larger quantities may still not affect airflow, but might induce cough that contributes markedly to patient morbidity [32]. In asthma, there are two main potential consequences of abnormal airway mucus: airway obstruction and increased airway responsiveness.
Epidemiology of mucus hypersecretion in asthma
The detrimental effects of excess mucus on airway mucociliary clearance, luminal patency and airway reactivity outlined above should have concomitant detrimental effects on the asthmatic patient. Certainly, phlegm production (indicative of airway mucus hypersecretion) is an index of poor asthma control [2]. The greatest risk for increased mortality in asthma is decreased lung function, with a significant proportion of the excess risk associated with mucus hypersecretion [1]. Some of the
Generation of the airway mucus hypersecretory phenotype in asthma
Most of the numerous inflammatory mediators produced in asthmatic airways, together with neural mechanisms, can theoretically generate the mucus hypersecretory phenotype in asthma. In experimental studies, these mediators and neural mechanisms increase mucin secretion, induce plasma exudation, upregulate MUC gene expression, increase mucin synthesis and cause goblet cell hyperplasia (summarized in Table 1) 43., 44., 45.. Th2 lymphocyte-mediated generation of the mucus hypersecretory phenotype
Pharmacotherapy of mucus pathophysiology in asthma
Airway mucus contributes to morbidity and mortality in many asthmatic patients; consequently, drugs affecting the hypersecretory component of asthma should be beneficial in these patients. Asthma has specific trigger factors, its own ‘profile’ of pulmonary inflammation and its own mucus hypersecretory phenotype (Figure 2); therefore, specific drugs might be required to fulfil the objectives for treatment of hypersecretion in asthma (Table 2). Pharmacotherapy of airway mucus hypersecretion in
Conclusions
Airway mucus hypersecretion and the pathophysiological changes that accompany it are features of many patients with asthma. The impact of airway hypersecretion on morbidity and mortality is now more fully understood, even though it can often be limited to certain groups of patients. Nevertheless, it is important to develop drugs that inhibit mucus hypersecretion in susceptible patients. Before addressing these issues, more information is required on mucus physiology and pathophysiology,
Update
Induction of heme oxygenase, the enzyme that degrades heme, by repeated administrations of hemin demonstrates anti-inflammatory activity in a mouse model of allergic asthma, including inhibition of airway mucus hypersecretion (inhibition of upregulated MUC5AC gene expression and of increased periodic acid-Schiff staining of mucus) [56]. The inhibitory effects of hemin were reversed by the heme oxygenase inhibitor tin protoporphyrin-IX.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
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